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Resumen Objetivo Evitar el deterioro de los pacientes con fibromialgia por actuaciones perjudiciales en la practica clinica potencialmente evitables. Metodos Un panel multidisciplinar de expertos identifico las areas clave, analizo la evidencia cientifica y formulo las recomendaciones a partir de esta evidencia y de tecnicas cualitativas de «evaluacion formal» o «juicio razonado». Resultados Se han elaborado 39 recomendaciones sobre diagnostico, tratamientos no eficaces ni seguros, educacion del paciente y formacion del profesional. En esta parte II se reflejan las 12 recomendaciones, referidas a las dos ultimas areas. Conclusiones Un buen conocimiento de la fibromialgia por el paciente mejora el afrontamiento y la aceptacion de la enfermedad reduciendo la gravedad de algunas manifestaciones clinicas. Los profesionales sanitarios que tratan a los pacientes con fibromialgia deben tener una buena formacion sobre esta enfermedad para mejorar los resultados del tratamiento y la relacion con el paciente.

Resumen Objetivo Evitar el deterioro de los pacientes con fibromialgia por actuaciones perjudiciales en la practica clinica potencialmente evitables. Metodos Un panel multidisciplinar de expertos identifico las areas claves, analizo la evidencia cientifica y formulo las recomendaciones a partir de esta evidencia y de tecnicas cualitativas de «evaluacion formal» o «juicio razonado». Resultados Se han elaborado 39 recomendaciones sobre diagnostico, tratamientos no eficaces ni seguros, educacion del paciente y formacion del profesional. En esta parte I se reflejan las 27 primeras, referidas a las 2 primeras areas. Conclusiones Establecer el diagnostico mejora el afrontamiento del paciente y reduce los costes sanitarios. Se deben evitar AINE, opioides mayores y benzodiacepinas por los efectos adversos. No existe una evidencia solida que justifique la asociacion de farmacos. Tampoco existe una buena evidencia para recomendar ningun tipo de terapia complementaria. Las cirugias muestran mas complicaciones y un grado de satisfaccion menor por el paciente por lo que deben evitarse si la indicacion no esta claramente establecida.

Objective To prevent the impairment of fibromyalgia patients due to harmful actions in daily clinical practice that are potentially avoidable. Methods A multidisciplinary team identified the main areas of interest and carried out an analysis of scientific evidence and established recommendations based on the evidence and “formal evaluation” or “reasoned judgment” qualitative analysis techniques. Results A total of 39 recommendations address diagnosis, unsafe or ineffective treatment interventions and patient and healthcare workers’ education. This part I shows the first 27 recommendations on the first 2 areas. Conclusions Establishing a diagnosis improves the patient's coping with the disease and reduces healthcare costs. NSAIDs, strong opioids and benzodiazepines should be avoided due to side effects. There is no good evidence to justify the association of several drugs. There is also no good evidence to recommend any complementary medicine. Surgeries show a greater number of complications and a lower degree of patient satisfaction and therefore should be avoided if the surgical indication is not clearly established.

Background Obesity among persons living with HIV (PLWH) has increased and weight gain after antiretroviral therapy (ART) can lead to metabolic disorders and impact survival. Our objective was to analyze weight and metabolic changes in HIV näive patients after 48 weeks of ART. Methods Observational, retrospective, multicentered cohort study comprising naïve-patients who started tenofovir alafenamide/emtricitabine/elvitegravir/cobicistat (TAF/FTC/EVG/c) or abacavir/lamivudine/dolutegravir (ABC/3TC/DTG), with no change in treatment for 48 weeks. Clinical and metabolic parameters were collected at baseline and week-48. Statistical program used was SPSS 21.0.0. Results The study included 329 participants from 6 hospitals. Participants were 89% male and 10% had AIDS diagnosis. Median age was 35 (IQR 27–43) years. Median baseline CD4 count was 417 (IQR 250–569) cell/mm3 and HIV viral load 4.65 (IQR 4.21–5.18) log10 copies/ml. Baseline median weight was 70 (IQR 62–79) kg, body mass index 23.4 (IQR 21.2–26.0) kg/m2; 22.7% overweight and 6.4% obese. ART regimens: ABC/3TC/DTG (196), TAF/FTC/EVG/c (133). Baseline characteristics were similar in both ART groups. Average weight gain at week-48 was 2.9 (SD 5.5) kg ( p < 0.0001) with no differences between both groups. There was an increase in obesity (6.4%–8%; p < 0.003) and overweight (22.7%–28.9%; p < 0.0001). Weight increase was associated with AIDS: OR 3.05 (95%; CI 1.009–9.22), p = 0.048; and lower baseline weight: OR 1.032 (95% CI 1.009–1.05), p = 0.006. Conclusions After ART initiation patients gain weight regardless of the regimen they take. Weight gain is associated with AIDS and the use of TAF/FTC/EVG/c.

[Objectives] Real world data on glecaprevir/pibrentasvir (G/P) among active drug users are scarce. We evaluated the sustained virological response (SVR) rates of G/P among individuals with and without active drug use in routine clinical practice., [Methods] Two ongoing prospective multicenter cohorts of individuals starting G/P were analyzed. Overall SVR intention-to-treat (ITT), discontinuations due to adverse effects and dropouts were evaluated. Results in patients with active, past and without active drug use were compared., [Results] Overall, 644 individuals started G/P and have reached the date of SVR evaluation. Of them, 613 (95.2%) individuals achieved SVR. There were two (0.3%) relapses, one (0.2%) discontinuation due to side effects and 35 (5.4%) dropouts. SVR rates for patients with active drug use, past drug use and those who never used drugs were 85.4%(n/N = 70/82), 96.1%(n/N = 320/333) and 97.4%(n/N = 223/229) respectively (p < 0.001). After adjustment by sex, age, HCV genotype and opioid agonist therapy, active drug use was the only factor independently associated with SVR (ITT) [adjusted OR (95%confidence interval): 0.29(0.09–0.99),p = 0.048]., [Conclusions] Active drug use was independently associated with lower SVR rates to G/P, mainly due to voluntary dropout. G/P could be particularly beneficial in this scenario but specific strategies designed to increase the retention in care are needed., This study has been funded by Instituto de Salud Carlos III through the project “PI018/00606″ (Co-funded by European Regional Development Fund/European Social Fund "A way to make Europe"/"Investing in your future"). This work was supported by the Ministry of Science, Innovation and Universities of Spain for A.G.-S and A.R.-J who are recipients of a Miguel Servet Research Contract (CP18/00146 and CP18/00111), co-financed by the FSE ‘El Fondo Social Europeo invierte en tu futuro’. A.C.-G. has received a Rıo Hortega grant from the Instituto de Salud Carlos III (CM19/00251) and a research extension grant Acción B, Acción para el Refuerzo de la Actividad Investigadora en las Unidades Clínicas del Servicio Andaluz de Salud 2021, Clínicos Investigadores (grant number B-0061-2021). J.A.P. has received a research extension grant from the Programa de Intensificacion de la Actividad de Investigacion del Servicio Nacional de Salud Carlos III (3SNS). J.M. has received a research extension grant Acción A, Acción para el Refuerzo anual de la Actividad Investigadora en las Unidades Clínicas del Servicio Andaluz de Salud 2021(grant number A1-0060-2021).

The paper focuses on the design of urban digital transformation strategies. It builds upon the lessons learned from the Digital Cities Challenge initiative, developed by the European Commission, de...

Anti-neuroinflammatory treatment has gained importance in the search for pharmacological treatments of different neurological and psychiatric diseases, such as depression, schizophrenia, Parkinson’s disease, and Alzheimer’s disease. Clinical studies demonstrate a reduction of the mentioned diseases’ symptoms after the administration of anti-inflammatory drugs. Novel coumarin derivates have been shown to elicit anti-neuroinflammatory effects via G-protein coupled receptor GPR55, with possibly reduced side-effects compared to the known anti-inflammatory drugs. In this study, we, therefore, evaluated the anti-inflammatory capacities of the two novel coumarin-based compounds, KIT C and KIT H, in human neuroblastoma cells and primary murine microglia. Both compounds reduced PGE2-concentrations likely via the inhibition of COX-2 synthesis in SK-N-SH cells but only KIT C decreased PGE2-levels in primary microglia. The examination of other pro- and anti-inflammatory parameters showed varying effects of both compounds. Therefore, the differences in the effects of KIT C and KIT H might be explained by functional selectivity as well as tissue- or cell-dependent expression and signal pathways coupled to GPR55. Understanding the role of chemical residues in functional selectivity and specific cell- and tissue-targeting might open new therapeutic options in pharmacological drug development and might improve the treatment of the mentioned diseases by intervening in an early step of their pathogenesis.

GEHEP-004 Study Group: María Dolores Ocete, Miguel Ángel Simón, Pilar Rincón, Sergi Reus, Alberto De la Iglesia, Isabel García-Arata, Miguel Jiménez, Fernando Jiménez, José Hernández-Quero, Carlos Galera, Mohamed Omar Balghata, Joaquín Primo, Mar Masiá, Nuria Espinosa, Marcial Delgado, Miguel Ángel von-Wichmann, Antonio Collado, Jesús Santos, Carlos Mínguez, Felícitas Díaz-Flores, Elisa Fernández, Enrique Bernal, José De Juan, José Joaquín Antón, Mónica Vélez, Antonio Aguilera, Daniel Navarro, Juan Ignacio Arenas, Clotilde Fernández, María Dolores Espinosa, María José Ríos, Roberto Alonso, Carmen Hidalgo, Rosario Hernández, María Jesús Téllez, Francisco Javier Rodríguez, Pedro Antequera, Cristina Delgado, Patricia Martín, Javier Crespo, Berta Becerril, Óscar Pérez, Antonio García-Herola, José Montero, Carolina Freyre, Concepción Grau., [Background & Aims] Most hepatitis C virus (HCV)-infected patients failing NS5A inhibitors develop resistance-associated substitutions (RASs). Here we report the use of resistance-guided retreatment of patients who failed prior NS5A inhibitor-containing regimens in the GEHEP-004 cohort. This is the largest direct-acting antiviral (DAA)-resistance cohort study conducted in Spain. We aim to provide indications on how to use resistance information in settings where sofosbuvir/velpatasvir/voxilaprevir may not be available., [Methods] GEHEP-004 is a prospective multicenter cohort enrolling HCV-infected patients treated with interferon (IFN)-free DAA regimens. Prior to retreatment, population-based sequencing of HCV NS3, NS5A and NS5B genes was performed. After receiving a comprehensive resistance interpretation report, the retreatment regimen was chosen and the sustained virological response (SVR) at 12 weeks after treatment completion (SVR12) was recorded., [Results] A total of 342 patients experiencing virological failure after treatment with sofosbuvir/ledipasvir±ribavirin (54%), sofosbuvir/daclatasvir±ribavirin (23%), or paritaprevir-ritonavir/ombitasvir±dasabuvir±ribavirin (20%) were studied. After a resistance report, 186 patients were retreated. An SVR12 was achieved for 88.1% of the patients who failed after sofosbuvir/ledipasvir±ribavirin, 83.3% of the patients who failed after sofosbuvir/daclatasvir±ribavirin, 93.7% of the patients who failed after paritaprevir-ritonavir+ombitasvir±dasabuvir±ribavirin., [Conclusions] In our study, we show how resistance-guided retreatment in conjunction with an interpreted report allows patients to achieve SVR rates close to 90%. We hypothesize that SVR rates may even be improved if resistance data are discussed between experienced virologists and treating clinicians. We believe that our data may be relevant for countries where the access to new DAA combination regimens is limited., [Lay summary] Hepatitis C infection can be cured with currently available antiviral agents. Only a small proportion of patients experience treatment failure, however, in absolute numbers, a high number of patients may require retreatment. Highly effective combinations of antivirals are also available for retreatment. However, these antivirals might not be available in resource-limited settings. Herein, we show how, by analyzing the cause of resistance, retreatment efficacy with old drugs can get very close to the efficacy of new drug combinations., This work was supported in part by grants from Fondo de Investigación Sanitaria (www.isciii.es) (PI15/00713), Plan Nacional de I+D+I and Fondo Europeo de Desarrollo Regional-FEDER (www.redes/redes/inicio) (RD16/0025/0040), Fundación Progreso y Salud, Junta de Andalucia (http://www.juntadeandalucia.es/fundacionprogresoysalud/es) (PI-0411-2014), and GEHEP-SEIMC (GEHEP-004).

ZUsammenfassungBereits früher publizierte Daten zeigten günstige Effekte von Thymian bei entzündlichen Prozessen. Um diese Erkenntnisse zu vertiefen, wurde in verschiedenen experimentellen Modellen ein Thymianextrakt auf die hier zugrundeliegenden molekularbiologischen Mechanismen in vitro untersucht. Nachgewiesen wurde eine Hemmung der LPS-induzierten Zytokin-Freisetzung von IL-1β, PGE2 sowie TNF-α in humanen Monozyten, eine Hemmung der LPS-induzierten Phosphorylierung und eine Aktivierung von IκBα sowie eine Inhibition der Transkriptionsaktivität von NF-κB und AP-1 in der Bronchialepithel-Zelllinie A549. Ein weiterer interessanter Befund war eine antagonistische Aktivität des untersuchten Thymianextraktes am TRPA1-Rezeptor, ein Rezeptor, der Hustenreize vermitteln kann. Die Anwendung des Thymianextraktes bei Erkältungs- bzw. Bronchitis-bedingtem Husten, bei dem entzündliche Prozesse auf bzw. in der Schleimhaut involviert sind, darf daher als plausibel gelten.

Background & Aims People who inject drugs (PWID) and are on opioid agonist therapy (OAT) might have lower adherence to direct-acting antivirals (DAAs) against hepatitis C virus (HCV) and, therefore, lower rates of sustained virologic response (SVR). Because of this, we compared the SVR rates to interferon-free DAA combinations in individuals receiving OAT and those not receiving OAT in a real-world setting. Methods The HEPAVIR-DAA cohort, recruiting HIV/HCV-coinfected patients (NCT02057003), and the GEHEP-MONO cohort (NCT02333292), including HCV-monoinfected individuals, are ongoing prospective multicenter cohorts of patients receiving DAAs in clinical practice. We compared SVR 12 weeks after treatment (SVR12) in non-drug users and PWID, including those receiving or not receiving OAT. Intention-to-treat and per protocol analyses were performed. Results Overall, 1,752 patients started interferon-free DAA treatment. By intention-to-treat analysis, 778 (95%, 95% CI 93%–96%) never injectors, 673 (92%, 95% CI 89%–93%) PWID not on OAT and 177 (89%, 95% CI 83%–92%) PWID on OAT achieved SVR12 (p = 0.002). SVR12 rates for ongoing drug users (with or without OAT) were 68 (79%) compared with 1,548 (95%) for non-drug users (p Conclusions HCV-infected PWID achieve high SVR12 rates with DAAs whether they are on OAT or not, but their response rates are lower than those of patients who never used drugs. This is mainly attributable to more frequent loss to follow-up. Accounting for active drug use during DAA therapy nearly closed the gap in SVR rates between the study groups. Lay summary Patients with hepatitis C virus infection who are on opioid agonist therapy can achieve high cure rates with current treatments. The use of illicit drugs during treatment can drive drop-outs and reduce cure rates. However, hepatitis C can be cured in most of those using drugs who complete treatment and follow-up. Clinical trial number: HEPAVIR-DAA cohort, NCT02057003; GEHEP-MONO cohort, NCT02333292.

To the scarce information on dietary habits in fibromyalgia (FM), it is added that there are no comparative studies with other rheumatic diseases. The objective of this study was to characterise the dietary habits of patients with FM by comparing, for the first time, with healthy controls (HC) and rheumatoid arthritis (RA).This cross-sectional, observational study was based on data obtained from the Dietfibrom project for FM and from the IMID Consortium for RA and HC. All participants completed a food frequency questionnaire evaluating their weekly dietary intake of main food groups. The three cohorts were compared using a multiple logistic regression model adjusted for age, sex, and body mass index.After quality control, n=287 FM, n=1,983 HC and n=1,942 RA patients were analysed. We found that FM had a profound impact in the diet compared to HC, reducing the consumption of dairy (OR=0.32, p0.0001), bread and/or whole grain cereals (OR=0.59, p=0.0006), fresh fruit (OR=0.66, P=0.008), and fish (OR=0.64, p=0.002). These same four food groups were also significantly reduced in FM patients in comparison to RA patients (p0.0005 in all cases). Additionally, a lower consumption of pasta, rice and/or potatoes was also observed in FM compared to RA (OR=0.72, p=0.028).The present cross-sectional study shows that FM is associated to a significant change in the normal dietary patterns. These results underscore the importance of diet in this prevalent disease and are a warning of the potential long-range effects of a deficient nutritional status.

In the medical literature, there are only a few references on refractory fibromyalgia and there is no consensus definition available on this concept. Some definitions of refractory fibromyalgia have been proposed based on the lack of response to a number of medications, and perhaps the most appropriate term is treatment-refractory fibromyalgia. To achieve the definition of treatment-refractory fibromyalgia, it is necessary to consider several previous steps, such as making sure the diagnosis has been made properly and a differential diagnosis with entities that can mimic fibromyalgia symptoms (including complete physical examination and laboratory test) has been made. The possibility that another factor that alters the response to treatment should be investigated, and in particular review all prescribed medication and search for some non-medical reasons that could mask the response to treatment (e.g., legal compensation). The definition of refractory fibromyalgia is complex and probably should include a lack of response to a specified number of drugs or to combination therapy with at least two non-pharmacological measures. In this article, it is not our purpose to present a formal definition, but to raise the possible bases for this purpose. We believe that it is a subject that must be discussed extensively before reaching a consensus definition. Key Points • There is no appropriate definition to classify fibromyalgia patients who do not respond to the usual pharmacological and non-pharmacological measures according to the national or international guidelines. • A consensus definition is required to classify these patients, which could help standardize future management strategies. In this article, we propose the bases on which refractory fibromyalgia could be defined.

Human cannabinoid receptor type 1 (hCB(1)R) plays important roles in the regulation of appetite and development of addictive behaviors. Herein, we describe the design, synthesis, photocharacterization, molecular docking, and in vitro characterization of “photo-rimonabant”, i.e., azo-derivatives of the selective hCB(1)R antagonist SR1411716A (rimonabant). By applying azo-extension strategies, we yielded compound 16a, which shows marked affinity for CB(1)R (K(i (cis form)) = 29 nM), whose potency increases by illumination with ultraviolet light (CB(1)R K(i)trans/cis ratio = 15.3). Through radioligand binding, calcium mobilization, and cell luminescence assays, we established that 16a is highly selective for hCB(1)R over hCB(2)R. These selective antagonists can be valuable molecular tools for optical modulation of CBRs and better understanding of disorders associated with the endocannabinoid system.

Objective To prevent the deterioration of patients with fibromyalgia due to potentially avoidable harmful actions in clinical practice. Methods A multidisciplinary panel of experts identified key areas, analysed the scientific evidence and formulated recommendations based on this evidence and qualitative techniques of “formal assessment” or “reasoned judgement”. Results Thirty-nine recommendations were made on diagnosis, ineffective and unsafe treatments, patient education and practitioner training. This part II shows the 12 recommendations, referring to the latter two areas. Conclusions Good knowledge of fibromyalgia on the part of patients improves their coping and acceptance of the disease and reduces the severity of some clinical manifestations. Healthcare professionals treating patients with fibromyalgia should be well trained in this disease to improve treatment outcomes and patient relationships.

Tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) are pro-inflammatory cytokines involved in acute and chronic inflammatory diseases. Indeed, immunotherapy blocking these 2 cytokines has been developed. Micro-immunotherapy (MI) also uses ultra-low doses (ULD) of pro-inflammatory cytokines, impregnated on lactose-sucrose pillules, to counteract their overexpression. The study has been conducted with 2 objectives: examine the anti-inflammatory effect in vitro and the capacity of 2 unitary medicines, TNF-α (27 CH) and IL-1β (27 CH), to reduce the secretion of TNF-α in human primary monocytes and THP-1 cells differentiated with phorbol-12-myristate-13-acetate, after lipopolysaccharide (LPS) exposure; then, investigate the presence of particles possibly containing starting materials using tunable resistive pulse sensing technique. The results show that the unitary medicines, tested at 3 pillules concentrations (5.5, 11 and 22 mM), have reduced the secretion of TNF-α in both models by about 10−20% vs. vehicle control, depending on concentration. In this exploratory study, particles (150−1000 nm) have been detected in MI ULD-impregnated pillules and a hypothesis for MI medicines mode of action has been proposed. Conscious that more evaluations are necessary, authors are cautious in the conclusions because the findings described in the study are still limited, and future investigations may lead to different hypothesis.

Background Comparative genomics methods enable the reconstruction of bacterial regulatory networks using available experimental data. In spite of their potential for accelerating research into the composition and evolution of bacterial regulons, few comparative genomics suites have been developed for the automated analysis of these regulatory systems. Available solutions typically rely on precomputed databases for operon and ortholog predictions, limiting the scope of analyses to processed complete genomes, and several key issues such as the transfer of experimental information or the integration of regulatory information in a probabilistic setting remain largely unaddressed. Results Here we introduce CGB, a flexible platform for comparative genomics of prokaryotic regulons. CGB has few external dependencies and enables fully customized analyses of newly available genome data. The platform automates the merging of experimental information and uses a gene-centered, Bayesian framework to generate and integrate easily interpretable results. We demonstrate its flexibility and power by analyzing the evolution of type III secretion system regulation in pathogenic Proteobacteria and by characterizing the SOS regulon of a new bacterial phylum, the Balneolaeota. Conclusions Our results demonstrate the applicability of the CGB pipeline in multiple settings. CGB’s ability to automatically integrate experimental information from multiple sources and use complete and draft genomic data, coupled with its non-reliance on precomputed databases and its easily interpretable display of gene-centered posterior probabilities of regulation provide users with an unprecedented level of flexibility in launching comparative genomics analyses of prokaryotic transcriptional regulatory networks. The analyses of type III secretion and SOS response regulatory networks illustrate instances of convergent and divergent evolution of these regulatory systems, showcasing the power of formal ancestral state reconstruction at inferring the evolutionary history of regulatory networks.

Objective: Burnout among physicians has increased, affecting not only doctors but also the quality of patient care. Treating challenging disorders, such as fibromyalgia, may increase the risk of feeling burned out. Health care of fibromyalgia patients is increasingly being assigned to family physicians. Therefore, we described the demographic characteristics, work contexts, component burnout scores (exhaustion, depersonalization, and personal accomplishment), and perceptions of fibromyalgia care of Spanish family medicine physicians with high and low levels of burnout. We then evaluated which of these variables were associated with having high or low levels of burnout. Method: This cross-sectional study assessed 506 family physicians recruited from the Spanish Society of Family Physicians and randomly selected from Primary Health Care Centers. The subgrouping of family physicians based on their burnout scores was assessed by cluster analysis. Variables showing statistically significant differences between clusters and significance below 0.25 in univariate logistic regressions were assessed by multivariate logistic regression analysis. Results: Family physicians reporting higher burnout scores (25%) felt that fibromyalgia patients on sick leave increased their workload, reported no support from nurses in the treatment of fibromyalgia patients, and had a more negative impression of fibromyalgia patients. Conclusions: One-quarter of family physicians reported feeling exhausted, detached from fibromyalgia patients, or less professionally accomplished. Several personal characteristics and contextual variables increased burnout. Several interventions to modify these variables and, thus, protect family physicians treating fibromyalgia from burnout are suggested.

Supplemental_Material._Floris_et_al._revised_26.08.20 for Pro-Inflammatory Cytokines at Ultra-Low Dose Exert Anti-Inflammatory Effect In Vitro: A Possible Mode of Action Involving Sub-Micron Particles? by Ilaria Floris, Thorsten Rose, Juan Antonio Collado Rojas, Kurt Appel, Camille Roesch and Beatrice Lejeune in Dose-Response

We present here one of the first cases of virological failure during treatment with bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). On March 2019, an antiretroviral-experienced HIV-infected patient was admitted to hospital because of cerebral toxoplasmosis. After undergoing treatment with sulfadiazine-pyrimethamine for two weeks, the patient initiated a BIC/FTC/TAF treatment, with 6.01 HIV RNA Log copies/mL, and 37 CD4 cells/μL. After two months under antiretroviral therapy (ART), acute neurologic deterioration with epilepsy, right hemiparesis and dysphagia occurred, leading to nasogastric nutrition and treatment. After several weeks, virological failure was confirmed with 4.01 HIV RNA Log copies/mL and R263K and M184V resistance mutations were detected.

[EN] Research Question: This article clarifies the role of clusters in industry agglomeration efficiency as well as the role that public and private agents play in their efficiency. Motivation: The automobile industry in Spain is an exception to the industrial decline suffered by the secondary sector since the economic crisis exploded in Spain. Employment in the vehicle manufacturing industry has recovered significantly in Spain in 2017, with a significant growth bringing it closer to 2008 levels. The sector accounts for 8.6 % of the country's GNP. How can we explain this success? Are there new threats (technology, environmental standards, emerging economies, etc.) menacing the sector? Based on value chain and cluster theories we explain its success and how new threats could be managed? The response lays in analyzing the role of cluster agents in the various clusters dynamics. The research shows how the openness of clusters plays a crucial role in their sustainability. Idea: Based on value chain and cluster theories we explain their success and how new threats could be managed? The response lays in analyzing the role of cluster agents in the various clusters dynamics. The research shows how the openness of clusters plays a crucial role in their sustainability. Data: primary data was collected in two surveys and interviews campaigns during 2013 and 2017. Furthermore, secondary data from national, regional and sectoral sources were analysed. Tools: The research is based on a series of interviews and visits to the automotive clusters in Spain. Additionally, the authors have analyzed abundant secondary information and web contents available on the clusters agents: manufacturers, suppliers, unions, associations, etc. Findings: The paper concludes that regional and national policies are relevant but that consensus between clusters¿ agents is essential for their success. However, will the existing agents be able to withstand new threats? .Contribution: The article contributes to clusters literature and the clusters¿ role of the agents in the global value chain context. It also sheds light on public policies to support automotive industries. Limitations are linked to resource limitations., This research study has been supported by various national organizations (MINETUR; CDTI; ANFAC, SERNAUTI) as well as regions such as clusters associations around Spain.

Little data are available on renal toxicity exerted by direct-acting antivirals (DAAs) in real life. The aim of this study was to assess the impact of direct-acting antivirals against hepatitis C virus infection currently used in Spain and Portugal on the estimated glomerular filtration rate (eGFR) in clinical practise. From an international, prospective multicohort study, patients treated with DAAs for at least 12 weeks and with eGFR ≥30 mL/min per 1.73 m2 at baseline were selected. eGFR was determined using the CKD-EPI formula. A total of 1131 patients were included; 658 (58%) were HIV/HCV-coinfected patients. Among the 901 patients treated for 12 weeks, median (interquartile range) eGFR was 100 (87-107) at baseline vs 97 (85-105) mL/min per 1.73 m2 at week 12 of follow-up (FU12) post-treatment (P 60 mL/min per 1.73 m2 at baseline, 22 (2%) had eGFR

OBJECTIVES: Anaemia is the most common side effect associated with ribavirin (RBV). This study intended to assess its incidence and determine its predictive factors in patients with hepatitis C virus on RBV plus direct-acting antiviral agents (DAAs). METHODS: A retrospective study of patients receiving RBV+DAA was conducted. Serum haemoglobin (Hb) was determined at baseline and monitored 4 weekly. Anaemia was defined as a single occurrence of Hb

[Objectives]: Our objective was to identify patient factors associated with being untreated for hepatitis C virus (HCV) infection in HIV-coinfected patients., [Methods]: A prospective longitudinal study was carried out. HIV-infected patients with active chronic HCV infection included in the HERACLES cohort (NCT02511496) constituted the study population. The main study outcome was receipt of HCV direct-acting antiviral (DAA) treatment from 1 May 2015 to 1 May 2017. The population was divided into patients who were receiving HCV treatment during follow-up and those who were not., [Results]: Of the 15 556 HIV-infected patients in care, 3075 (19.7%) presented with chronic HCV infection and constituted the study population. At the end of the follow-up, 1957 patients initiated HCV therapy (63.6%). Age < 50 years, absence of or minimal liver fibrosis, being treatment-naïve, HCV genotype 3 infection, being in the category of people who inject drugs using opioid substitutive therapy (OST-PWID), and being in the category of recent PWID were identified as significant independent risk factors associated with low odds of DAA implementation. When a multivariate analysis was performed including only the PWID population, both OST-PWID [odds ratio (OR) 0.552; 95% confidence interval (CI) 0.409–0.746) and recent PWID (OR 0.019; 95% CI 0.004–0.087) were identified as independent factors associated with low odds of treatment implementation., [Conclusions]: We identified factors, which did not include prioritization of a DAA uptake strategy, that limited access to HCV therapy. The low treatment uptake in several populations seriously jeopardizes the elimination of HCV infection in the coming years., This work was supported by the Ministerio de Sanidad (RD12/0017/0012) integrated in the Plan Nacional de I+D+I, and cofinanced by the ISCIII‐Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER), the Fundación para la Investigación en Salud (FIS) del Instituto Carlos III (PI15/01017), and the Red de Investigación en SIDA de España ISCIII‐RETIC (grant number: RD16/0025/0034).

[Objectives] To compare the efficacy of sofosbuvir/ledipasvir (SOF/LDV) for 8 weeks (SL8) versus a 12-week course of SOF/LDV (SL12) among HIV/HCV-coinfected patients in clinical practice. In addition we compared sustained virological response (SVR) rates achieved with SL8 in HCV-monoinfected and HIV/HCV-coinfected patients in a real life setting., [Methods] HCV-infected patients were retrospectively selected from the HEPAVIR-DAA and GEHEP-MONO real-life prospective cohorts if they fulfilled the following criteria: 1) Infected with genotype 1; 2) Treatment with SL8 or SL12; 3) Treatment naïve prior to receiving SL8 or SL12; 4) Absence of cirrhosis; 5) Baseline HCV RNA, [Results] In the SL8 group, 107 (51%) HCV-monoinfected and 102 (49%) HIV/HCV-coinfected patients were included. One hundred and sixty-four (43%) HCV-monoinfected subjects and 220 (57%) HIV/HCV-coinfected patients received SL12. SVR12 rates for HIV/HCV-coinfected patients treated with SL8 vs SL12 were SVR12 92.2% vs. 97.3% (p = 0.044) and the respective relapse rates were 4.9% vs. 0.5% (p = 0.013). SVR12 rates for SL8 among HCV-monoinfected and HIV/HCV-coinfected patients were: 96.3% vs. 92.2% (p = 0.243), respectively. The corresponding relapse rates were 0.9% vs. 4.9% (p = 0.112)., [Conclusion] HIV/HCV-coinfected patients reach high rates of SVR12 with SL8, although lower than with SL12, mainly due to a higher probability of relapse. SVR12 rates with SL8 are numerically lower and the proportion of relapses higher in HIV/HCVcoinfected patients than in HCV-monoinfected subjects., This study was partly supported by the projects “PI15/01607” and “PI16/01443”, funded by Instituto de Salud Carlos III, integrated in the national I+D+i 2013-2016 and co-funded by European Union (ERDF/ESF, “Investing in your future”) and by the Grupo para el Estudio de las Hepatitis Víricas (GEHEP) (grant GEHEP 001 2017). J.M. is the recipient of a grant from the Servicio Andaluz de Salud de la Junta de Andalucía (grant number B-0037). J.A.P. is recipient of an intensification grant from the Instituto de Salud Carlos III (grant number Programa-I3SNS). This work has been partially funded by the Spanish AIDS Research Network RD16/0025/0010 and RD16/0025/0034 - ISCIII – FEDER.

OBJECTIVE To estimate the prevalence of fibromyalgia among women with endometriosis and analyze the effect of fibromyalgia on health-related quality of life (HRQoL). METHODS An observational case-control study conducted at a tertiary hospital in Barcelona between April 2015 and March 2017 among women with deep infiltrating endometriosis (DIE; n=80), women with superficial endometriosis or ovarian endometrioma (non-DIE; n=76), and control women without endometriosis (n=73). Fibromyalgia was assessed via the London Fibromyalgia Epidemiological Study Screening Questionnaire (LFESSQ). HRQoL was evaluated with the 36-Item Short Form (SF-36) questionnaire. The impact of fibromyalgia and other clinical characteristics was assessed by multivariate regression analysis. RESULTS More women fulfilled the criteria for fibromyalgia in the DIE group than in the non-DIE and control groups by LFESSQ-4 (31 [39%], 12 [16%], and 6 [8%], respectively; P=0.009) and LFESSQ-6 (22 [28%], 8 [11%], and 4 [5%], respectively; P=0.008). The DIE group reported significantly poorer HRQoL for all SF-36 dimensions. Women with DIE who fulfilled the criteria for fibromyalgia had lower physical component scores (-31.6; 95% confidence interval, -50.8 to -12.3; P=0.003). CONCLUSION The estimated prevalence of fibromyalgia was higher among women with DIE. Women with DIE and positive fibromyalgia screening had lower HRQoL.

Background Data on the efficacy, safety, and concomitant use with other drugs of the combination ritonavir-boosted paritaprevir/ombitasvir plus dasabuvir (PrOD) in HIV/HCV-coinfected patients in real life are limited. The objectives of this study were to analyze these topics in HIV/HCV-coinfected subjects bearing HCV genotype 1 (GT1). Methods One hundred and eighty-two HIV/HCV-coinfected patients with GT1 (87 1a, 71 1b, 23 other) treated with PrOD, plus ribavirin (RBV) in 119 cases, in routine clinical practice were analyzed. The main variable of efficacy was sustained virological response (SVR) 12 weeks after completing therapy in an intention-to-treat (ITT) analysis and that of safety treatment discontinuation because of adverse effects. Factors associated with SVR were analyzed with a modified ITT (mITT) strategy. Results One hundred and seventy-two (94%) patients attained SVR, 3 (2%) experienced a relapse and two (1%) discontinued therapy due to adverse events. The rates of SVR in subjects with GT 1a and 1b by mITT were, respectively, 97% and 98%. Sixty-five (98%) out of 66 patients with cirrhosis and 107 (98%) out of 110 (p = 1) non-cirrhotics achieved SVR. Fifty-five (95%) patients on concomitant darunavir therapy developed SVR vs. 117 (99%) (p = 0.105) of those without DRV. RBV dose was reduced in 13 (11%) patients and permanently discontinued in 2 (2%), with no impact on SVR. Conclusions PrOD is highly effective and well tolerated in HIV/HCV-coinfected patients with GT1 in routine clinical practice. RBV is often required. However, RBV dose reduction or discontinuation is uncommonly needed and do not impair the SVR rate.

6 Páges, 1 Figure, 1 Table. The online version of this article (https://doi.org/10.1007/s10048-017-0524-6) contains supplementary material, which is available to authorized users., In two siblings, who suffer from an early childhood-onset axonal polyneuropathy with exclusive involvement of motor fibers, the c.629T>C (p.F210S) mutation was identified in the X-linked AIFM1 gene, which encodes for the apoptosis-inducing factor (AIF). The mutation was predicted as deleterious, according to in silico analysis. A decreased expression of the AIF protein, altered cellular morphology, and a fragmented mitochondrial network were observed in the proband's fibroblasts. This new form of motor neuropathy expands the phenotypic spectrum of AIFM1 mutations and therefore, the AIFM1 gene should be considered in the diagnosis of hereditary motor neuropathies., This project was funded by the Instituto de Salud Carlos III (ISCIII)–FEDER (grant nos. PI12/00453 and PI15/00187). P.S. has a FPU grant funded by the Ministerio de Educación, Cultura y Deporte (grant no. FPU15/00964). A.S.M. has a grant funded by the Fundació per amor a l’art (FPAA). C.E. has a BMiguel Servet^ contract funded by the ISCIII and Centro de Investigación Príncipe Felipe (CIPF) (grant no. CPII14/00002). The Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) is an initiative from the ISCIII.

Phylogenetic studies are a valuable tool to understand viral transmission patterns and the role of immigration in HIV-1 spread. We analyzed the spatio-temporal relationship of different HIV-1 non-B subtype variants over time using phylogenetic analysis techniques. We collected 693 pol (PR+RT) sequences that were sampled from 2005 to 2012 from naïve patients in different hospitals in southern Spain. We used REGA v3.0 to classify them into subtypes and recombinant forms, which were confirmed by phylogenetic analysis through maximum likelihood (ML) using RAxML. For the main HIV-1 non-B variants, publicly available, genetically similar sequences were sought using HIV-BLAST. The presence of HIV-1 lineages circulating in our study population was established using ML and Bayesian inference (BEAST v1.7.5) and transmission networks were identified. We detected 165 (23.4%) patients infected with HIV-1 non-B variants: 104 (63%) with recombinant viruses in pol: CRF02_AG (71, 43%), CRF14_BG (8, 4.8%), CRF06_cpx (5, 3%) and nine other recombinant forms (11, 6.7%) and unique recombinants (9, 5.5%). The rest (61, 37%) were infected with non-recombinant subtypes: A1 (30, 18.2%), C (7, [4.2%]), D (3, [1.8%]), F1 (9, 5.5%) and G (12, 7.3%). Most patients infected with HIV-1 non-B variants were men (63%, p < 0.001) aged over 35 (73.5%, p < 0.001), heterosexuals (92.2%, p < 0.001), from Africa (59.5%, p < 0.001) and living in the El Ejido area (62.4%, p